tbuckley/cabot-search huggingface dataset:
Integrated proteogenomic characterization of urothelial carcinoma of the bladder
Authors: Ning Xu, Zhenmei Yao, Guoguo Shang, Dingwei Ye, Haixing Wang, Hailiang Zhang, Yuanyuan Qu, Fujiang Xu, Yunzhi Wang, Zhaoyu Qin, Jiajun Zhu, Fan Zhang, Jinwen Feng, Sha Tian, Yang Liu, Jianyuan Zhao, Jun Hou, Jianming Guo, Yingyong Hou, Chen Ding
Journal: Journal of Hematology & Oncology (2022)

Abstract Background Urothelial carcinoma (UC) is the most common pathological type of bladder cancer, a malignant tumor. However, an integrated multi-omics analysis of the Chinese UC patient cohort is lacking. Methods We performed an integrated multi-omics analysis, including whole-exome sequencing, RNA-seq, proteomic, and phosphoproteomic analysis of 116 Chinese UC patients, comprising 45 non-muscle-invasive bladder cancer patients (NMIBCs) and 71 muscle-invasive bladder cancer patients (MIBCs). Result Proteogenomic integration analysis indicated that SND1 and CDK5 amplifications on chromosome 7q were associated with the activation of STAT3, which was relevant to tumor proliferation. Chromosome 5p gain in NMIBC patients was a high-risk factor, through modulating actin cytoskeleton implicating in tumor cells invasion. Phosphoproteomic analysis of tumors and morphologically normal human urothelium produced UC-associated activated kinases, including CDK1 and PRKDC. Proteomic analysis identified three groups, U-I, U-II, and U-III, reflecting distinct clinical prognosis and molecular signatures. Immune subtypes of UC tumors revealed a complex immune landscape and suggested the amplification of TRAF2 related to the increased expression of PD-L1. Additionally, increased GARS, related to subtype U-II, was validated to promote pentose phosphate pathway by inhibiting activities of PGK1 and PKM2. Conclusions This study provides a valuable resource for researchers and clinicians to further identify molecular pathogenesis and therapeutic opportunities in urothelial carcinoma of the bladder.
SURG-17. Impact of introduction of sagittal dimensions to predictive model of post-operative cerebellar mutism (CMS): A report of the Nottingham CMS Workshop
Authors: David Walker, Jo-Fen Liu, Rob A Dineen, Ulrich-Wilhelm Thomale, Pablo Hernáiz Driever
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: The Nottingham-Liverpool risk stratification tool for predicting post-operative cerebellar mutism syndrome (CMS) requires further refinement. Previous smaller studies identified tumours arising in cerebellar hemispheres (CH+ve) as very low risk and proposed that larger sagittal dimensions may be associated with a higher CMS risk. METHODS: An international multi-centre workshop assembled clinical, imaging and surgical data from 242 posterior fossa tumour patients from 9 centres (age 2-23.8, mean 8.23 years; histology 122 medulloblastoma, 75 pilocytic astrocytoma, 25 ependymoma, 18 other tumour types, 2 not known). Post-operative CMS developed in 0/66 CH+ve and 40/176 CH-ve patients (23%, range 13-33%) and. Tumour measurements in the sagittal plane were incorporated into the predictive model. RESULTS: In CH-ve tumours, CMS was associated higher D-Sag (CMS+ve 3.91±1.08 vs CMS-ve 3.01±1.56 cm p=0.001), d-Sag (CMS+ve 0.63±0.27 vs CMS-ve 0.44±0.31 cm p=0.001) and D-Sag*d-Sag (CMS+ve 2.60±1.36 vs CMS-ve 1.65±1.45 cm2 p=0.001). The Rotterdam model identified CMS rates for CH-ve tumours for low, intermediate and high risk groups as: 4% (2/45), 20% (16/79) and 42% (22/52), respectively. CONCLUSIONS: Incorporating D-sag and d-Sag estimates of tumour size, proposed, and adopted by the Beijing and Rotterdam groups, respectively, enhanced the objectivity and supports the model’s CMS predictive capacity for the purposes of consent and future trials. Higher CMS risk, associated with larger sagittal dimensions, may account for variability in CMS rates between cohorts and, as a new finding, may have broader clinical implications around the timing of diagnosis.
Updates in the Treatment of Multiple Myeloma
Authors: Shaji K. Kumar
Journal: Journal of the National Comprehensive Cancer Network (2022)

For patients with newly diagnosed multiple myeloma (MM), treatment with 4-drug regimens produce deep responses and should be considered for those with high-risk features. Daratumumab + lenalidomide and dexamethasone is standard treatment for newly diagnosed patients not eligible for autologous stem cell transplantation (ASCT). Although lenalidomide remains standard maintenance therapy, in some instances more intensive regimens can be considered. ASCT is more effective when given up-front rather than delayed, but delaying transplantation until disease progression is acceptable. CAR T-cell therapy can provide durable responses, and 2 agents are now FDA-approved for use in multiple myeloma. Bispecific T-cell engagers are also effective for relapsed myeloma, as is the BCL2 inhibitor venetoclax, especially for patients with t(11;14) disease. An emerging novel class of drugs, the CELMoDs (cereblon E3 ligase modulator), target cereblon.
Impact of capecitabine maintenance on survival outcomes in triple-negative breast cancer patients not attaining pathological complete response following neoadjuvant chemotherapy: Real-world data from a tertiary care center from India.
Authors: Rakesh Kumar Sharma, Ajay Gogia, Hari Krishna Raju Sagiraju, S V Suryanarayana Deo, Dayanand Sharma, Sandeep Mathur
Journal: Journal of Clinical Oncology (2022)

e12593 Background: Capecitabine maintenance has demonstrated a survival benefit in triple-negative breast cancer (TNBC) patients not achieving pathological complete response (pCR) following neo-adjuvant chemotherapy (NACT). However, there is scarcity of data from Indian sub-continent corroborating the benefit of capecitabine maintenance. Methods: This retrospective study comprised of 161 TNBC patients registered at our institute between a period of May 2013 to Dec 2020, who received NACT (sequential anthracycline and taxane) but did not achieve pCR. Capecitabine was added to the institutional protocol since 2017 for maintenance therapy of TNBC patients who didn’t achieve pCR post NACT. Using Kaplan-Meir survival analysis and multivariate cox-proportional hazard models, we analysed differences in the relapse-free survival (RFS) and overall survival (OS) among those who received capecitabine maintenance therapy (n=80) versus those who did not receive it (n=81). Results: Distribution of age, family history, baseline performance score, tumor size, node positivity and clinical stage at time of presentation were comparable between the study groups, except for menopausal status (50% in control vs 33% in capecitabine group). Median(IQR) follow up time was 22.2 (16.2-27.4) months in capecitabine groups vs 19.3 (11.7-35.1) in control group. Twenty-three (28.8%) women in the capecitabine group had a disease-relapse while 45.7% (n=37) had relapsed in control group (p=0.026). Median RFS was 20.4 (17.8-25.9) months in control group while it was not reached in capecitabine group (log rank p=0.007). Adjusted for other baseline clinical characteristics, hazard of disease-relapse was significantly lower in the capecitabine group compared to controls [adjusted Hazard Ratio (aHR), 95% CI: 0.57 (0.34-0.96), p=0.035]. Median OS was not achieved in both the study groups, however, the hazard of death was lower in capecitabine group compared to control [aHR(95%CI): 0.44 (0.20-1.01), p-0.053]. Stratified by menopausal status, effect of capecitabine maintenance on disease relapse and RFS was only significant among the post-menopausal women [aHR (95%CI): 0.24 (0.10-0.59)]. Conclusions: This is the first study from our country, demonstrating a survival benefit with capecitabine maintenance in patients with TNBC not achieving pCR following NACT, particularly in post-menopausal women. It is an important observation as most of our patients present with locally advanced disease where pCR rate is low.
Implementation and efficacy of a fellow-led, case-based noon lecture series.
Authors: James Dickerson, Nathaniel James Myall, Mohana Roy, Tyler Paul Johnson
Journal: Journal of Clinical Oncology (2022)

11011 Background: For new fellows, learning clinical oncology represents an enormous challenge. Few data support specific didactic approaches. The senior author (TPJ) developed a novel curriculum, emphasizing deliberate practice as part of a design grounded in Ericsson’s “expert performance approach”. These noon conferences are case based with a focus on key clinical trials and NCCN guidelines. In comparison to didactics given directly by faculty, these conferences are primarily presented by a senior teaching fellow with an invited faculty member adding additional commentary as an “expert discussant”. We surveyed fellows to assess perception of efficacy and also created a board style test to evaluate knowledge gains. Methods: The curriculum began in 2020. After one year, we surveyed fellows with a five-point likert scale survey to quantify their perception of the curriculum. In 2022, we created a pair of 18-question lung cancer specific board style tests for the five teaching sessions on lung cancer. Prior to the first conference, the pre-test was sent to fellows electronically; after the final lecture the other 18-question test was sent out. Differences in the overall cohort’s test score were examined via a paired student t-test. Results: On the 2021 survey, 59% of fellows responded (17 of 29). Of the respondents, 83% attended at least half of the lectures (14 of 17). When asked to compare this conference series to traditional lecture-based series, 59% (10 of 17) agreed with the statement that "this series is one of the very best I've encountered" and all said it was at least “better than average.” 94% of respondents (16 of 17) said the series equipped them for clinical practice to either a “significant” or “remarkable” degree. 94% of respondents (16 of 17) agreed the conferences helped them learn to “think like oncologists.” For the five session lung cancer block, fellows reported attending an average of 3.6 ± 1.4 sessions (n = 13). On the 18-question pre-test (n = 19), the average score ± one standard deviation was 73% ± 15%. For the post-test (n = 13), the average was 68% ± 17% (p = 0.48). Conclusions: We developed a novel curriculum to replace traditional didactics. Fellows perceived the curriculum to be exceptionally strong as compared to traditional lecture series, felt it prepared them well for practice, and said it taught them to think like oncologists. Pre/post knowledge assessments did not show an improvement in knowledge. Distribution to larger numbers of fellows–especially early learners–may better power a study to detect improvements in learning.
Symptoms and psychosocial distress associated with malignant wounds: Secondary analysis of a prospective cohort study.
Authors: Shigemasa Takamizawa, Hiroto Ishiki, Shunsuke Oyamada, Daisuke Kiuchi, Koji Amano, Eriko Satomi
Journal: Journal of Clinical Oncology (2022)

e24008 Background: Symptoms associated with malignant wounds (MWs) worsen a patient's quality of life. However, MWs’ impact on psychosocial health and end-of-life status is unknown. Methods: This is a secondary analysis of the results of a large prospective cohort study conducted in 23 palliative care units in Japan. Consecutive patients were enrolled and followed up until their death or for six months. Patient demographics, symptom burden, medication use, and MW status were documented on admission. Healthcare professionals rated the symptoms using the Integrated Palliative care Outcome Scale (IPOS), a 5-point Likert scale. Quality of death (QOD) was evaluated at death using the Good Death Scale (GDS). The primary outcome was the prevalence of severe psychological symptom burden, evaluated as an IPOS-feeling score of 2–4. Factors that affected psychological symptoms and their relationship with GDS were also investigated. Results: Among the 1896 enrolled patients, 156 (8.2%) had MWs. MWs predominantly affected females and younger patients, and the most common primary sites were the breast (28.2%) and head and neck (19.2%). Among the patients with MWs, 75 (50.3%), 59 (39.6%), and 42 (28.2%) had exudate, pain, and bleeding, respectively. Among the 32 patients with MWs requiring dressing change at least twice a day and 117 patients with MWs requiring dressing change less than once a day, 20 (62.5%) and 44 (37.6%) had an IPOS-feeling score of 2–4, respectively (p = .015). Patients with MWs required antidepressants and opioids more frequently and received higher doses of opioids. Between the patients with and without MW, there were significant differences in IPOS-feeling and pain scores but not in breathlessness, fatigue, anorexia, somnolence, or dry mouth scores. IPOS-feeling and pain scores were worse in patients with MWs. Patients without MWs did not have better GDS scores (p = .48). Conclusions: Patients with MWs frequently required antidepressants and opioids, suggesting an increased prevalence of depression and severe pain. Psychological distress was influenced by the frequency of dressing changes. The presence of MWs did not affect the QOD.[Table: see text]
Single-cell RNA sequencing reveals evolution of immune landscape during glioblastoma progression
Authors: Alan T. Yeo, Shruti Rawal, Bethany Delcuze, Anthos Christofides, Agata Atayde, Laura Strauss, Leonora Balaj, Vaughn A. Rogers, Erik J. Uhlmann, Hemant Varma, Bob S. Carter, Vassiliki A. Boussiotis, Al Charest
Journal: Nature Immunology (2022)

Abstract Glioblastoma (GBM) is an incurable primary malignant brain cancer hallmarked with a substantial protumorigenic immune component. Knowledge of the GBM immune microenvironment during tumor evolution and standard of care treatments is limited. Using single-cell transcriptomics and flow cytometry, we unveiled large-scale comprehensive longitudinal changes in immune cell composition throughout tumor progression in an epidermal growth factor receptor-driven genetic mouse GBM model. We identified subsets of proinflammatory microglia in developing GBMs and anti-inflammatory macrophages and protumorigenic myeloid-derived suppressors cells in end-stage tumors, an evolution that parallels breakdown of the blood–brain barrier and extensive growth of epidermal growth factor receptor + GBM cells. A similar relationship was found between microglia and macrophages in patient biopsies of low-grade glioma and GBM. Temozolomide decreased the accumulation of myeloid-derived suppressor cells, whereas concomitant temozolomide irradiation increased intratumoral GranzymeB + CD8 + T cells but also increased CD4 + regulatory T cells. These results provide a comprehensive and unbiased immune cellular landscape and its evolutionary changes during GBM progression.
Intratumoral immunotherapy relies on B and T cell collaboration
Authors: Idit Sagiv-Barfi, Debra K. Czerwinski, Tanaya Shree, Julian J. K. Lohmeyer, Ronald Levy
Journal: Science Immunology (2022)

Antitumor T cell responses are the primary mediators of cancer immunotherapy. However, many other components of the immune system are needed for efficient T cell responses to be generated. Here, we developed a combinatorial approach where a Toll-like receptor 9 agonist (CpG) and Fc-fused IL-12 protein were injected together into just one of several tumor sites in a mouse. This combination led to body-wide (abscopal) therapeutic responses in multiple cancer models. These systemic responses were dependent not only on T cells but also on B cells. B cells were activated by the treatment and were required for optimal T cell activation. This cross-talk was dependent on MHC and was tumor antigen specific. The addition of an agonistic antibody against OX40 further enhanced T cell activation and therapeutic responses. Our data suggest that the combination of CpG, anti-OX40, and IL-12Fc may have success in patients with cancer and that B and T cell collaboration is crucial for the efficacy of this combination immunotherapy.
Immune cell molecular pharmacodynamics of lanreotide in relation to treatment response.
Authors: Sabah Alaklabi, Orla Maguire, Hans Minderman, Renuka V. Iyer
Journal: Journal of Clinical Oncology (2022)

e16213 Background: Lanreotide is clinically effective in advanced neuroendocrine tumors (NETs). The inhibitory effect of lanreotide on tumor cells proliferation is due to binding to somatostatin receptors (SSTR1-5). It has been demonstrated that immune cells express SSTR1-5 differentially. The exact effect of somatostatin analogs (SSAs) on T cells function is not understood. Methods: In vitro and in vivo effects of lanreotide on immune cells were investigated, with regards to clinical response correlates. In vitro, SSTR1-5 expression was measured on CD4+ T helper cells, CD8+ cytotoxic T cells, and CD4+CD25+ T regulatory cells from healthy donors (HD), and lanreotide effect on key functional immune response parameters (NFkB, NFAT, ERK1/2 signaling, IFN, and IL-2 production) were studied. To assess in vivo effects of lanreotide on immune cells of NET pts, peripheral blood mononuclear cells (n = 16) obtained pre and 3 months post treatment were studied for gene and protein expression profiles in sorted T cell subsets using a NanoString immune cell panel. Results: HD T cells had high expression of SSTR2 and low/no expression of the other SSTRs. In vitro, lanreotide had no effect on the functional immune response parameters investigated. For the in vivo study, the patient cohort consisted of 8 responders (no progression by 19 months) and 8 non-responders. Clinicopathological features, see table. Pretreatment immunological competence of responders was greater than non-responders, as indicated by upregulation of TCR signaling (in CD4+) and interferon signaling (in CD8+ and T reg). Irrespective of clinical response, lanreotide had most significant effect on CD8+ T cells, down regulating WNT, TCR, and NF-kB signaling. Compared to non-responders, responders had down regulation of cytokine and chemokine signaling but upregulation of ubiquitination and proteasome degradation associated genes. Several myeloid specific genes were found to be significantly changed in the CD4 T helper population, possibly due to co isolated myeloid cells interacting with T cells during sorting. Conclusions: The in vivo immune effects of lanreotide seen reflect the relevance of parameters in tumor microenvironment such as interactions with myeloid components of the immune system not accounted for under the experimental in vitro conditions.[Table: see text]
DIPG-54. p53 pathway reactivation as a therapeutic strategy in diffuse intrinsic pontine glioma
Authors: Leslie Lupien, Veronica Rendo, Eric Morin, Nicholas Khuu, Jeromy DiGiacomo, Prasidda Khadka, Madison Chacon, Sophie Lu, Kristine Pelton, Lara Elcavage, Jaldeep Langhnoja, Keith Ligon, Rameen Beroukhim, Timothy Phoenix, Pratiti Bandopadhayay
Journal: Neuro-Oncology (2022)

Abstract TP53 is the most frequently mutated tumor suppressor with somatic alterations found in approximately 50% of all human cancers. In the remaining TP53 wild-type (WT) tumors, functional inactivation of the p53 pathway may be achieved through a variety of other mechanisms, including gene deletion, epigenetic silencing, and/or alterations in prominent negative regulators, including MDM2/MDM4 and PPM1D. These alterations block p53 activity and lead to uncontrolled cell proliferation and oncogenesis in a majority of cancers, including the highly aggressive, universally fatal glial cell tumors of childhood, known as Diffuse Intrinsic Pontine Gliomas (DIPGs). DIPGs are inoperable due to their location within the brainstem. Available treatment options, including radiotherapy, have had a palliative effect at best, with almost all children succumbing to the disease within 18 months of diagnosis. Recent advances have led to an improved understanding of the biological underpinnings of this disease and identification of recurrent genetic alterations that represent potential therapeutic targets for these patients. Prominent among these targets in DIPGs with WT p53 status (50%) are MDM2/4 and PPM1D, whose suppression lead to p53 reactivation specifically in the WT p53 context. We have undertaken a combination of approaches to better understand the therapeutic potential of MDM2 and PPM1D inhibition in DIPG, characterizing the genomic, transcriptomic, and cell-state changes that drive resistance, and identifying novel vulnerabilities that can be exploited with combination therapies towards a cure.
Evolution of Eczema, Wheeze, and Rhinitis from Infancy to Early Adulthood: Four Birth Cohort Studies
Authors: Sadia Haider, Sara Fontanella, Anhar Ullah, Stephen Turner, Angela Simpson, Graham Roberts, Clare S. Murray, John W. Holloway, John A. Curtin, Paul Cullinan, Syed Hasan Arshad, Guillem Hurault, Raquel Granell, Adnan Custovic, John Ainsworth, Andrew Boyd, Philip Couch, Graham Devereux, Ibrahim Emam, Yi-ke Guo, Sejal Saglani, Ashley Woodcock
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

The relationship between eczema, wheeze or asthma, and rhinitis is complex, and epidemiology and mechanisms of their comorbidities is unclear.
Characterization of tumor responses in patients (pts) with unresectable hepatocellular carcinoma (uHCC) treated with lenvatinib in REFLECT.
Authors: Masatoshi Kudo, Shukui Qin, Fabio Piscaglia, Arndt Vogel, T.R. Jeffry Evans, Jennifer J. Knox, Carlos López López, Zahra Ramji, Min Ren, Kalgi Mody, Richard S. Finn
Journal: Journal of Clinical Oncology (2022)

4078 Background: In REFLECT, lenvatinib was noninferior to sorafenib based on overall survival in pts with uHCC (median 13.6 vs 12.3 mos; hazard ratio [HR] 0.92, 95% CI 0.79–1.06). The objective response rate (ORR) with lenvatinib was 18.8% by blinded independent imaging review (IIR) per RECIST v1.1; ORR was 40.6% by blinded IIR per mRECIST. Here we further characterize the tumor responses in pts with uHCC who were treated with lenvatinib in REFLECT. Methods: Assessments of ORR included all pts randomly assigned to lenvatinib treatment (12 mg/day for bodyweight ≥60 kg or 8 mg/day for bodyweight &lt;60 kg). Time to first objective response (TTR) and duration of response (DOR) were calculated among pts who achieved a partial or complete tumor response. Tumors were assessed by IIR per RECIST v1.1 or mRECIST. Median DOR was estimated with the Kaplan-Meier product-limit method; 95% CI was estimated with a generalized Brookmeyer and Crowley method. Results: 478 Pts were randomly assigned to receive lenvatinib. Among the 90 pts (18.8%) who achieved an objective response by IIR per RECIST v1.1, median TTR was 2.8 mos (range 1–29) and median DOR was 7.4 mos (95% CI 5.6–9.2). Of the 194 pts who had an objective response by IIR per mRECIST, median TTR was 1.9 mos (range 1–15) and median DOR was 7.3 mos (95% CI 5.6–7.4). ORRs by selected baseline characteristics are reported in the Table. Notably, among responders by IIR per RECIST v1.1 (n=90), median overall survival (by Simon-Makuch method) was 23.4 mos (95% CI 17.6–26.3), median duration of treatment was 10.3 mos, and 65.6% of pts experienced grade ≥3 treatment-related adverse events. Conclusions: Pts with uHCC treated with lenvatinib achieved objective responses with a similar frequency to those seen with single-agent immune checkpoint inhibitors. These responses occurred irrespective of baseline characteristics. Tumor responses occurred early and were durable. Clinical trial information: NCT01761266. [Table: see text]